AB1508 A NOVEL PATHOGENIC VARIANT IN ZNF462 GENE ASSOCIATED WITH WEISS-KRUSZKA SYNDROME AND SLE
Authors: M. Constantinou, M. Lampi, V. Neocleous, P. Fanis, L. A. Phylactou, S. Psarelis, K. Parperis
Journal: Annals of the Rheumatic Diseases (2022)

Background Weiss-Kruszka syndrome (WSKA) is an autosomal dominant congenital anomaly syndrome due to mutations in the ZNF462 gene and manifests with developmental delay and multiple craniofacial abnormalities with variable expressivity 1 . It is also characterized by cognitive impairment, whilst about a third of the affected individuals belong to the autism spectrum. Although the disease is inherited with the autosomal dominant manner, most of the described subjects (95%) had de novo variants with no affected family members 1 . WSKA has been recently described and only 26 (including our patient) affected individuals have been classified to date 2 . Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of autoantibodies and multi-organ inflammation. Genetic factors might play an important role in disease pathogenesis in patients with childhood-onset SLE. Objectives To describe the case of a SLE patient who was found to have WSKA related to a novel pathogenic autosomal dominant (AD) variant in the ZNF462 gene, and inform clinicians of a possible association between the 2 conditions. Methods A 25-year-old Caucasian female with a history of SLE, diagnosed at the age of 14, manifested with malar rash, Raynaud’s phenomenon, arthritis, thrombocytopenia, positive ANA, ds-DNA antibody and hypocomplementemia. At the age of 17, she developed renal dysfunction due to lupus nephritis class IV, and she was treated with glucocorticoids (GCs), cyclophosphamide and hydroxychloroquine. In Oct 2020, she was admitted to the hospital for thrombotic thrombocytopenic purpura due to lupus exacerbation. She was successfully treated with GCs, plasma exchange and rituximab. During her hospitalization, the presence of various clinical features raised the suspicion of a genetic syndrome. First, the patient exhibited dysmorphic features such as hypertelorism, prognathism, arched eyebrows, flattened nasal bridge, small upper lip, mild intellectual disability, and a history of childhood-onset SLE. Whole exome sequencing (WES) by NGS was used for the genetic investigation of the patient. Figure 1. Results The patient underwent genetic evaluation with WES and the novel heterozygous AD pathogenic variant c.4142delT (p.lle1381ThrfsTer16) in ZNF462 gene was identified. Confirmation of the identified variant was also verified by sanger sequencing. Pathogenic variants in the ZNF462 gene were previously described in patients with the recently reported WSKA of which several characteristics are compatible with our patient’s features. The ZFN462 encodes a zinc-finger transcription factor that plays a role in embryonic development, transcriptional regulation, and chromatin remodelling. Given that chromatin remodelling has been implicated in the pathogenesis of SLE, the association of this novel ZNF462 variant in the development of SLE, needs to be determined 3 . Conclusion This is the first report of a patient with coexisting SLE and WSKA due to a novel variant. It illustrates the need for further research in order to elucidate any possible pathophysiologic link among the 2 conditions. References [1]Weiss K, Wigby K, Fannemel M, Henderson LB, Beck N, Ghali N, Study DDD, Anderlid BM, Lundin J, Hamosh A, Jones MC, Ghedia S, Muenke M, Kruszka P. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Eur J Hum Genet. 2017 Aug;25(8):946-951. doi: 10.1038/ejhg.2017.86. Epub 2017 May 17. PMID: 28513610; PMCID: PMC5567153. [2]Park J, Ha DJ, Seo GH, Maeng S, Kang SM, Kim S, Lee JE. Empty Sella Syndrome Associated with Growth Hormone Deficiency: the First Case Report of Weiss-Kruszka Syndrome. J Korean Med Sci. 2021 May 10;36(18):e133. doi: 10.3346/jkms.2021.36.e133. PMID: 33975400; PMCID: PMC8111047. [3]Surace AEA, Hedrich CM. The Role of Epigenetics in Autoimmune/Inflammatory Disease. Front Immunol. 2019 Jul 4;10:1525. doi: 10.3389/fimmu.2019.01525. PMID: 31333659; PMCID: PMC6620790. Disclosure of Interests None declared